MAPK4 predicts poor prognosis and facilitates the proliferation and migration of glioma through the AKT/mTOR pathway.
MAPK4 predicts poor prognosis and facilitates the proliferation and migration of glioma through the AKT/mTOR pathway.
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DOI：
10.1002/cam4.5859
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发表时间：
2023-05
期刊：
影响因子：
4
通讯作者：
Sun, Jinmin
中科院分区：
文献类型：
--
作者：
Ren, Jing;Zheng, Shijun;Zhang, Lei;Liu, Jia;Cao, Haowei;Wu, Sicheng;Xu, Yixin;Sun, Jinmin
丝裂原活化蛋白激酶4 （MAPK4）是丝裂原活化蛋白激酶（MAPK）家族的非典型成员。我们在此报告MAPK4在胶质瘤中过表达。MAPK4在胶质瘤中的临床意义、生物学作用和潜在的分子机制尚不清楚。基于肿瘤基因组图谱（TCGA）和中国胶质瘤基因组图谱（CGGA）数据库获得的数据，并通过免疫组织化学方法证实了MAPK4在胶质瘤患者中的表达和相关生存率。通过基因集富集分析（GSEA）和基因本体（GO）分析MAPK4的功能和途径富集。使用CCK8和transwell检测MAPK4沉默的多形性胶质母细胞瘤（GBM）细胞的活力和迁移能力，并使用流式细胞术进行细胞周期和凋亡分析。免疫印迹法分析MAPK4敲除胶质瘤细胞中的蛋白水平。我们还分析了MAPK4表达与胶质瘤中免疫浸润和免疫检查点的相关性。MAPK4在IDH野生型（wt）和1p/19q非编码胶质瘤中过表达。MAPK4表达预测胶质瘤患者预后不良。在单细胞分辨率下，MAPK4与胶质瘤的干性、转移、细胞周期、分化和增殖等功能状态有显著关系。MAPK4沉默通过AKT/mTOR途径抑制胶质瘤细胞的增殖和迁移，并诱导G1细胞周期阻滞。在体内，MAPK4敲低可显著抑制原发性胶质瘤的生长。此外，MAPK4的表达与浆细胞样DC细胞、CD8+ T细胞和T辅助细胞的浸润呈负相关。此外，MAPK4的表达与胶质瘤中主要免疫抑制剂检查点分子和一些趋化因子的表达呈正相关。MAPK4作为胶质瘤的预后指标，通过AKT/mTOR通路促进GBM细胞的增殖和迁移。MAPK4可能参与胶质瘤微环境中免疫浸润和免疫检查点的表达。MAPK4通过AKT/mTOR通路促进GBM细胞的增殖和迁移。在GBM中异常过表达的MAPK4激活AKT（T308）以及mTORC2、AKT（S473）和PKC的下游分子。AKT和PKC的磷酸化促进了gbm细胞的增殖和迁移。MAPK4通过AKT激活的机制促进GBM细胞的增殖和迁移。
Mitogen‐activated protein kinase 4 (MAPK4) is an atypical member of the mitogen‐activated protein kinase (MAPK) family. We report here that MAPK4 is overexpressed in glioma. The clinical significance, biological roles and underlying molecular mechanisms through which MAPK4 acts in glioma remain unclear. Analysis of MAPK4 expression and associated survival in glioma patients was performed based on data obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases and confirmed in human glioma tissue by immunohistochemistry. MAPK4 function and pathway enrichment were analyzed through Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO). The viability and migration ability of MAPK4‐silenced glioblastoma multiforme (GBM) cells were evaluated using CCK8 and transwell assays, respectively, and cell cycle and apoptosis analyses were performed using flow cytometry. Immunoblotting was used to analyze the protein level in MAPK4 knockdown glioma cells. We also analyzed the correlation of MAPK4 expression with immune infiltration and immune checkpoints in glioma. MAPK4 was overexpressed in IDH wild‐type (wt) and 1p/19q non‐codeletion gliomas. MAPK4 expression predicted poor prognosis of glioma patients. MAPK4 was significantly related to functional states, including stemness, metastasis, cell cycle, differentiation and proliferation, in glioma at single‐cell resolution. MAPK4 silencing inhibited proliferation and migration and induced G1 cell cycle arrest in glioma cells via the AKT/mTOR pathway. In vivo, MAPK4 knockdown markedly suppressed the growth of primary glioma. In addition, MAPK4 expression correlated negatively with the infiltration of plasmacytoid DC cells, CD8+ T cells and T helper cells. Moreover, MAPK4 expression correlated positively with expression of the main immunoinhibitor checkpoint molecules and some chemokines in glioma. MAPK4 functions as a prognostic indicator in glioma and promotes the proliferation and migration of GBM cells through the AKT/mTOR pathway. MAPK4 may participate in immune infiltration and the expression of immune checkpoints in the glioma microenvironment. MAPK4 promotes the proliferation and migration of GBM cells by AKT/mTOR pathway. Aberrantly overexpressed MAPK4 in GBM activates AKT(T308) and the downstream molecules of mTORC2, AKT(S473) and PKC. Thephosphorylation of AKT and PKC promotes the proliferation and migration of GBMcells. MAPK4 promotes the proliferation and migration of GBM cells through amechanism involving AKT activation.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
循环肿瘤细胞在免疫治疗中的新作用。
影响因子：
12.4
作者：
Rzhevskiy A;Kapitannikova A;Malinina P;Volovetsky A;Aboulkheyr Es H;Kulasinghe A;Thiery JP;Maslennikova A;Zvyagin AV;Ebrahimi Warkiani M
通讯作者：
Ebrahimi Warkiani M
影响因子：
16
作者：
Runkle KB;Kharbanda A;Stypulkowski E;Cao XJ;Wang W;Garcia BA;Witze ES
通讯作者：
Witze ES
影响因子：
4.8
作者：
Aberg, Espen;Perander, Maria;Seternes, Ole-Morten
通讯作者：
Seternes, Ole-Morten
影响因子：
4.8
作者：
Kant, Shashi;Schumacher, Stefanie;Gaestel, Matthias
通讯作者：
Gaestel, Matthias